Sulfide catabolism ameliorates hypoxic brain injury

• DOI: 10.1038/s41467-021-23363-x
• Publication Date: 2021-05-25T10:02:59Z
• Authors: Eizo Marutani; Masanobu Morita; Shuichi Hirai; Shinichi Kai; Robert M. H. Grange; Yusuke Miyazaki; Fumiaki Nagashima; Lisa Traeger; Aurora Magliocca; Tomoaki Ida; Tetsuro Matsunaga; Daniel R. Flicker; Benjamin Corman; Naohiro Mori; Yumiko Yamazaki; Annabelle Batten; Rebecca Li; Tomohiro Tanaka; Takamitsu Ikeda; Akito Nakagawa; Dmitriy N. Atochin; Hideshi Ihara; Benjamin A. Olenc...; Xinggui Shen; Motohiro Nishida; Kenjiro Hanaoka; Christopher G. Kevil; Ming Xian; Donald B. Bloch; Takaaki Akaike; Allyson G. Hindle; Hozumi Motohashi; Fumito Ichinose
• Keywords: Male; 0301 basic medicine; Science; Article; Rats, Sprague-Dawley; Mice; 03 medical and health sciences; Animals; Hydrogen Sulfide; Quinone Reductases; Hypoxia; Cells, Cultured; Membrane Potential, Mitochondrial; Mice, Knockout; Neuroscience and Neurobiology; Q; Brain; NAD; Mitochondria; Rats; 3. Good health; Mice, Inbred C57BL; Mice, Inbred DBA; Brain Injuries; Female; RNA Interference

AbstractThe mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.